Cks (Cdc kinase subunit) proteins were originally identified through their ability to genetically suppress defective alleles of the cyclin-dependent kinases (CDKs) of both fission and budding yeast. Subsequent investigations demonstrated that these small (9-18kD) proteins were ubiquitous in eukaryotes and could directly bind to CDK/cyclin complexes, hence the designation Cks. Humans and other mammals express two Cks paralogs, which are often overexpressed in cancer, which in some cases is associated with aggressive disease and poor survival. Yet neither the precise essential function(s) of these proteins nor their role in oncogenesis have been elucidated. The current proposal aims to use molecular and molecular genetic approaches to determine the essential functions of Cks1 and Cks2 in mammalian cells. Furthermore, the cellular effects of Cks protein overexpression will be explored to elucidate the link to malignancy. Finally, mouse tumor models will be used to determine if partial loss of Cks protein function can be protective against malignancy, potentially validating functional interactions between Cks proteinprotein as therapeutic targets.